Project Summary Recent studies have shown surprising tumor-suppressive roles for classically pro-oncogenic proteins in the initiation and progression of hepatocellular carcinoma (HCC). These findings may begin to explain why oncoprotein-targeting therapeutics have had little effect clinically, so elucidation of the mechanisms behind these surprising activities will be needed to develop more effective therapeutic strategies. Among these ?paradoxical tumor suppressors? are the phosphatase Shp2, which is required for full Ras/Erk signaling activation, and the kinase Ikk?, which is needed for activation of pro-inflammatory and anti-apoptotic NF-?B signaling. The objectives of this research are to elucidate the functional interactions of Shp2-dependent signaling and Ikk?-dependent NF-?B activities in the initiation and progression of HCC, and to identify the molecules that drive HCC in the absence of these usually pro-oncogenic pathways. By integrating pathological characterization and molecular analyses, this model will uncover tissue- and cellular-level pathology and signaling changes that drive HCC when major pro- oncogenic pathways such as Ras/Erk and NF-?B are disrupted. The results of this project will provide new understanding of the complex interactions between the usually pro-oncogenic signaling pathways that have been shown to suppress hepatocarcinogenesis in certain contexts, and may help identify mechanisms of relapse after targeted therapies.